Pharmaceutical compositions of lurasidone

ABSTRACT

Solid dispersions of lurasidone or a pharmaceutically acceptable salt thereof are described, as well as pharmaceutical formulations thereof, and methods for making such formulations. Preferably, the solid dispersions are prepared by hot-melt extrusion or spray-drying, and comprise lurasidone with a pharmaceutically acceptable carrier (e.g., hydroxypropyl methyl cellulose acetate succinate (HPMC-AS), polyvinyl pyrrolidine vinyl acetate (PVP/VA) copolymer, hydroxypropyl methylcellulose phthalate (HPMCP), or mixtures thereof). The pharmaceutical composition may be orally administered to a patient in either the fed or fasted state, with a decrease or elimination of the food effect. Preferably, following oral administration of the pharmaceutical compositions, there is no substantial difference in the pharmacokinetic parameters (e.g., T max , C max , AUC 0-t  and/or AUC 0-infinity ) of lurasidone, regardless of whether the pharmaceutical compositions are administered to a subject in the fed or fasted state.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/697,415, which claims foreign priority to Indian Application Nos. IN201941001273 and IN 201941002316, filed on Jan. 10, 2019 and Jan. 18,2019, respectively, each of which is incorporated by reference in itsentirety.

FIELD OF THE INVENTION

The present application relates to pharmaceutical compositionscomprising a lurasidone solid dispersion (e.g., an amorphous lurasidonesolid dispersion) and pharmaceutically acceptable excipient(s), as wellas methods for making such pharmaceutical compositions. The compositionsmay be administered in either the fed or fasted state. Advantageously,the pharmaceutical compositions according to the invention reduce oreliminate the food effect, which has been reported in connection withprior art formulations, e.g., as associated with thecommercially-available LATUDA® drug product.

The present application also provides methods for treating CNS disordersin a human, including schizophrenia and depressive episodes associatedwith bipolar disorder.

BACKGROUND OF THE INVENTION

Lurasidone is an antagonist with high affinity binding at the dopamineD2 receptors, serotonin 5-HT2A and 5-HT7 receptors. Lurasidone has thechemical nameN-4-4-(1,2-benzisothiazol-3-yl)-1-piperazinyl-(2R,3R)-2,3-tetramethylene-butyl-(1R,2S,3R,4'S)-2,3-bicyclo[2.2.1]heptanedicarboxyimide,and has the structural formula (I), shown below:

Formula (I)

Lurasidone, in the form of a free base or as an acid addition salt, isknown to have psychotropic activities and is effective as a therapeuticagent, particularly for schizophrenia or senile dementia. Seniledementia is broadly classified into Alzheimer's dementia andcerebrovascular dementia, and it can be said that the two make up about80% of senile dementia.

Lurasidone is very slightly soluble in water. Attaining sufficientbioavailability of this drug is problematic. It is estimated that about9-19% of an administered dose is absorbed in the fed state.

Lurasidone is currently marketed in the United States under the brandname LATUDA®, and is provided as 20 mg, 40 mg, 60 mg, 80 mg and 120 mgtablets for oral administration. LATUDA® must be administered with food(at least 350 calories), which substantially increases the absorption.For example, LATUDA® mean C_(max) and AUC values are increased by about3-times and 2-times, respectively, when administered with food comparedto the levels observed under fasting conditions.

Weight gain is a common adverse effect associated with atypicalantipsychotic drugs. As LATUDA® must be administered with food (at least350 calories), this further increases the weight gain adverse effect ofLATUDA®.

There remains a need for a composition and a dosage form exhibitingsuitable bioavailability, which substantially reduces or overcomes thedifferential between the bioavailability of the drug in patients who arefasted versus the bioavailability of the drug in patients who are fed,and/or which substantially can reduce or overcome the intra- and/orinter-individual variations observed with the commercial availableproducts.

Thus, there exists a need for the development of pharmaceuticallurasidone compositions, as well as methods of treatment, whichsuccessfully address or eliminate the food effect and/or provideimproved bioavailability.

SUMMARY OF THE INVENTION

The present application relates to pharmaceutical compositions oflurasidone that decrease or eliminate the food effect, which has beenproblematic with prior lurasidone formulations, such as the LATUDA® oraltablet drug product. In particular, the present application relates topharmaceutical compositions comprising lurasidone solid dispersion andpharmaceutically acceptable excipient(s), wherein the composition may beadministered in either fed or fasted state, and wherein the food effectis decreased or eliminated.

Certain aspects relate to compositions for oral administration thatprovide higher lurasidone bioavailability than commercially availableformulations such as LATUDA® in both a fed and fasted state, e.g.,compositions that yield higher plasma levels in both a fed and a fastedstate.

Specifically, the present application also provides compositions fororal administration that provide a therapeutically acceptable plasmalevel of lurasidone when administered to a patient in a fasted state.Thus, in certain aspects, the present application relates to improvedlurasidone pharmaceutical compositions, which exhibit improvedbioavailability in the fasting state, compared to the existingformulations, e.g., such as the commercially-available LATUDA® oraltablet drug product.

In certain embodiments, upon oral administration to a patient, thepharmaceutical compositions described herein exhibit less variability inpharmacokinetic parameters (e.g., T_(max), C_(max), AUC_(0-t) and/orAUC_(0-infinity)) between the fasted and fed states. For example,certain embodiments relate to compositions for oral administration thatprovide lurasidone to a patient population with lower variability inbioavailability (e.g., a narrower observed range for C_(max) and AUCvalues), thus providing consistent pharmacokinetic (PK) parametersacross a patient population to whom the formulation is administered.

In certain aspects, the application describes lurasidone compositionsthat are suitable for oral administration to patients, and which provideuniform plasma level(s) and therapeutically effective lurasidoneexposure, in fasted and/or fed states. The application also provideslurasidone compositions that exhibit less intra-subject variabilityand/or less inter-subject variability in pharmacokinetic parameters(e.g., T_(max), C_(max), AUC_(0-t) and/or AUC_(0-infinity)) thancommercially available lurasidone formulations, e.g., LATUDA®.

Preferably, following oral administration of said pharmaceuticalcomposition to subjects, there is no substantial difference in thepharmacokinetic parameters (e.g., T_(max), C_(max), AUC_(0-t) and/orAUC_(0-infinity)) of the lurasidone, regardless of whether thepharmaceutical composition is administered to a subject in fed or fastedstate. By “no substantial difference” is meant that the values for thepharmacokinetic parameters (e.g., T_(max), C_(max), AUC_(0-t) and/orAUC_(0-infinity)) are within about 70% to about 143% of each other,preferably within about 80 to about 125%.

The present invention provides a method for treatment or prevention ofCNS disorders, which comprises administering a solid oral dosage formcomprising an effective amount of lurasidone to a human in fasted state,wherein the area under the plasma concentration versus time curve(AUC_(0-inf)) of the lurasidone in the human subsequent to saidadministering is from 70% to 143% of the mean area under the lurasidoneplasma concentration versus time curve (AUC_(0-inf)) resulting fromadministration of control lurasidone oral tablets containing the sameamount of lurasidone to a cohort of humans in a fed state.

In one embodiment, the present invention provides a method for treatmentor prevention of a CNS disorder, which method comprises (a) providing apharmaceutical composition of lurasidone as described in the presentspecification to a human without regard to food, e.g., wherein thepharmaceutical compositions do not have a food effect; and (b)administering said pharmaceutical composition to a human, in needthereof, without regard to food.

In an embodiment, the invention relates to a pharmaceutical compositioncomprising a solid dispersion of amorphous lurasidone in apharmaceutically acceptable carrier, wherein the pharmaceuticallyacceptable carrier is a polymer selected from the group consisting ofhydroxypropyl methyl cellulose acetate succinate (HPMC-AS), polyvinylpyrrolidine vinyl acetate (PVP/VA) copolymer, hydroxypropylmethylcellulose phthalate (HPMCP), and mixtures thereof; and wherein thepharmaceutical composition may be administered to a human subject ineither fed or fasted state.

In an embodiment, pharmaceutical compositions are provided, wherein atleast one pharmacokinetic parameter in the fasted stated is from about70% to about 143% of the at least one pharmacokinetic parameter in thefed state; and wherein the at least one pharmacokinetic parameter isselected from (i) the area under the plasma concentration versus timecurve for total drug exposure (AUC_(0-infinity)), (ii) peak plasmaconcentration (C_(max)), (iii) time to reach C_(max) (T_(max)), (iv)area under the plasma concentration versus time curve at a certain time(t) after drug administration (AUC_(0-t)), or (v) combinations thereof.

In an embodiment, pharmaceutical compositions comprising a soliddispersion of amorphous lurasidone in a pharmaceutically acceptablecarrier are provided, wherein the pharmaceutically acceptable carrierfurther comprises a solubilizer, a surfactant, or a mixture thereof, andwherein the pharmaceutical composition may be administered to a humansubject in either fed or fasted state.

In an embodiment, pharmaceutical compositions comprising a soliddispersion of amorphous lurasidone in at least one pharmaceuticallyacceptable carrier are provided, wherein the in vitro dissolution rateis less than about 50% in 60 minutes, and wherein the in vitro releaserate is chosen such that the peak plasma levels of lurasidone obtainedin vivo occurs between about 1 and about 6 hours after administration ofthe composition to a patient. For example, the in vitro dissolution ratemay be determined using a USP paddle method of 75 rpm in 500 mL 0.1 NHCl at 37° C., or the in vitro dissolution rate may be determined usinga USP paddle method of 75 rpm in 1000 ml 4.5 pH acetate buffer at 37° C.

In an embodiment, pharmaceutical compositions comprising a soliddispersion of amorphous lurasidone in a pharmaceutically acceptablecarrier are provided, wherein at least one parameter in the fastedstated is from about 70% to about 143% of the at least onepharmacokinetic parameter in the fed state; and wherein the at least onepharmacokinetic parameter is selected from AUC_(0-infinity), C_(max),T_(max), AUC_(0-t), or combinations thereof.

In an embodiment, pharmaceutical compositions comprising a soliddispersion of amorphous lurasidone in a pharmaceutically acceptablecarrier are provided, wherein the solid dispersion optionally furthercomprises a solubilizer, a surfactant, or a mixture thereof, whereinsaid composition upon oral administration in fasting and fed statesexhibits bioequivalence to a commercially available reference lurasidonedrug product (such as LATUDA®), in the fed state, and wherein saidbioequivalence is established by at least one parameter that is selectedfrom (i) a confidence interval for mean AUC_(0-t) between about 70% andabout 143%; (ii) a confidence interval for mean AUC_(0-infinity) betweenabout 70% and about 143%; (iii) a confidence interval for mean C_(max)between about 70% and about 143%; (iv) a confidence interval for meanT_(max) between about 70% and about 143%; or (v) combinations thereof.Preferably, bioequivalence is established by at least one parameter thatis selected from (i) a confidence interval for mean AUC_(0-t) betweenabout 80% and about 125%; (ii) a confidence interval for meanAUC_(0-infinity) between about 80% and about 125%; (iii) a confidenceinterval for mean C_(max) between about 80% and about 125%; (iv) aconfidence interval for mean T_(max) between about 80% and about 125%;or (v) combinations thereof.

Each of embodiments above may further have one or more of the followingadditional elements in any combination:

Element 1: a pharmaceutical composition as described herein, whichcomprises a solid dispersion of amorphous lurasidone that is made byhot-melt extrusion, spray-drying or co-precipitation.

Element 2: a pharmaceutical composition as described herein, wherein thesolid dispersion of amorphous lurasidone has a weight ratio of thelurasidone or pharmaceutically acceptable salt thereof to thepharmaceutically acceptable carrier from about 1:1 to about 1:6,preferably from about 1:2 to about 1:4, most preferably about 1:3.

Element 3: a pharmaceutical composition as described herein, wherein thepharmaceutical composition comprises from about 50 mg to about 400 mg ofthe lurasidone or pharmaceutically acceptable salt thereof, preferably20 mg, 40 mg, 60 mg, 80 mg, 120 mg or 160 mg of lurasidonehydrochloride, or 18.62 mg, 37.24 mg, 55.87 mg, 74.49 mg or 111.74 mg oflurasidone free base.

Element 4: a pharmaceutical composition as described herein, wherein thepharmaceutical composition is in the form of a tablet, a capsule, acaplet, beads, granules or oral suspension.

Element 5: a pharmaceutical composition as described herein, wherein thepharmaceutical composition comprises granules of the solid dispersion ofamorphous lurasidone, and wherein the granules of the solid dispersionof amorphous lurasidone comprise lurasidone and HPMC-AS as apharmaceutically acceptable carrier.

Element 6: a pharmaceutical composition as described herein, wherein thepharmaceutical composition comprises granules of the solid dispersion ofamorphous lurasidone, and wherein the granules of the solid dispersionof amorphous lurasidone comprise at least a first portion of granulescomprising lurasidone and HPMC-AS, and at least a second portion ofgranules comprising lurasidone and PVP/VA copolymer.

Element 7: a pharmaceutical composition as described herein, wherein thepharmaceutical composition comprises granules of the solid dispersion ofamorphous lurasidone, and further comprising at least one extra-granularexcipient selected from the group consisting of microcrystallinecellulose, croscarmellose sodium (Ac-Di-Sol), colloidal silicon dioxide,and mixtures thereof; preferably wherein the at least one extra-granularexcipient comprises microcrystalline cellulose, croscarmellose sodium(Ac-Di-Sol), or mixtures thereof. More preferably, the at least oneextra-granular excipient consists essentially of, or consists of,microcrystalline cellulose, croscarmellose sodium (Ac-Di-Sol), andcolloidal silicon dioxide and/or the at least one extra-granularexcipient consists essentially of, or consists of, microcrystallinecellulose and croscarmellose sodium (Ac-Di-Sol).

Element 8: a pharmaceutical composition as described herein, wherein thepharmaceutical composition comprises granules of the solid dispersion ofamorphous lurasidone, and wherein the granules further comprise at leastone intra-granular excipient, preferably wherein the at least oneintra-granular excipient comprises microcrystalline cellulose,croscarmellose sodium (Ac-Di-Sol), colloidal silicon dioxide, ormixtures thereof. Preferably, the at least one intra-granular excipientconsists essentially of, or consists of microcrystalline cellulose,croscarmellose sodium (Ac-Di-Sol), and colloidal silicon dioxide.

Element 9: a pharmaceutical composition as described herein, which isobtained by direct compression, wet granulation or dry granulation.

Element 10: a pharmaceutical composition as described herein furthercomprising at least one excipient selected from the group consisting ofdiluents, binders, chelating agents, coating agents, disintegratingagents, lubricants, colorants, surfactants and mixtures thereof. Thesepharmaceutically acceptable excipients may be used in intra-granular orextra-granular portions.

Element 11: a method for treating a CNS disorder in a human, whichmethod comprises administering a pharmaceutical composition as describedherein to a patient in a fasted or fed state.

Element 12: a pharmaceutical composition as described herein, whereinthe pharmaceutical composition is in the form of a tablet, and whereinthe tablet comprises (a) granules of the solid dispersion of amorphouslurasidone, (b) at least one extra-granular excipient, and (c)optionally, a tablet coating.

Element 13: a pharmaceutical composition as described herein, whereinthe pharmaceutical composition comprises granules of a solid dispersionof amorphous lurasidone, and wherein the granules comprise lurasidone,hydroxypropyl methyl cellulose acetate succinate (HPMC-AS),hydroxypropyl cellulose (HPC), optionally sodium lauryl sulfate, andmixtures thereof. Preferably, the granules consist essentially of, orconsist of, lurasidone, hydroxypropyl methyl cellulose acetate succinate(HPMC-AS), hydroxypropyl cellulose (HPC), and optionally, sodium laurylsulfate.

Element 14: a pharmaceutical composition as described herein, whereinthe pharmaceutical composition comprises granules of a solid dispersionof amorphous lurasidone, and wherein the granules comprise lurasidone,hydroxypropyl methyl cellulose acetate succinate (HPMC-AS),hydroxypropyl cellulose (HPC), and optionally, sodium lauryl sulfate,and wherein the composition further comprises an extra-granular portioncontaining hydroxypropyl methyl cellulose acetate succinate (HPMC-AS),wherein the composition may be administered in the fed and/or fastedstate.

Element 15: a pharmaceutical composition as described herein, whereinthe pharmaceutical composition comprises granules of a solid dispersionof amorphous lurasidone, wherein the granules comprise lurasidone andhydroxypropyl methyl cellulose acetate succinate (HPMC-AS), and whereinthe composition further comprises an extra-granular portion containinghydroxypropyl methyl cellulose acetate succinate (HPMC-AS), wherein thecomposition may be administered in the fed and/or fasted state.

Element 16: a pharmaceutical composition as described herein, whereinthe pharmaceutical composition comprises granules of a solid dispersionof amorphous lurasidone, and further comprises at least oneextra-granular excipient selected from the group consisting ofmicrocrystalline cellulose, croscarmellose sodium (Ac-Di-Sol), colloidalsilicon dioxide, and mixtures thereof.

Element 17: a pharmaceutical composition as described herein, whereinthe AUC_(0-infinity) of lurasidone in a human subject subsequent toadministration in the fasted state is from about 70% to about 143% ofthe AUC_(0-infinity) of lurasidone in a human subject subsequent toadministration in the fed state, preferably wherein the AUC_(0-infinity)of lurasidone in a human subject subsequent to administration in thefasted state is from about 80% to about 125% of the AUC_(0-infinity) oflurasidone in a human subject subsequent to administration in the fedstate. Also covered is a pharmaceutical composition as described herein,wherein the AUC_(0-t) of lurasidone in a human subject subsequent toadministration in the fasted state is from about 70% to about 143% ofthe AUC_(0-t) of lurasidone in a human subject subsequent toadministration in the fed state, preferably wherein the AUC_(0-t) oflurasidone in a human subject subsequent to administration in the fastedstate is from about 80% to about 125% of the AUC_(0-t) of lurasidone ina human subject subsequent to administration in the fed state.

Element 18: a pharmaceutical composition as described herein, whereinthe C_(max) of lurasidone in a human subject subsequent toadministration in fasted state is from about 70% to about 143% of theC_(max) of lurasidone in a human subject subsequent to administration inthe fed state, preferably wherein the C_(max) of lurasidone in a humansubject subsequent to administration in fasted state is from about 80%to about 125% of the C_(max) of lurasidone in a human subject subsequentto administration in the fed state. Also covered is a pharmaceuticalcomposition as described herein, wherein the T_(max) of lurasidone in ahuman subject subsequent to administration in fasted state is from about70% to about 143% of the T_(max) of lurasidone in a human subjectsubsequent to administration in the fed state, preferably wherein theT_(max) of lurasidone in a human subject subsequent to administration infasted state is from about 80% to about 125% of the T_(max) oflurasidone in a human subject subsequent to administration in the fedstate.

Element 19: a pharmaceutical composition as described herein, whereinsaid composition upon oral administration in fasting and fed statesexhibits bioequivalence to a commercially available reference lurasidonedrug product (such as LATUDA®), in the fed state, and wherein saidbioequivalence is established by at least one of: (i) a confidenceinterval for mean AUC_(0-t) between about 70% and about 143%; (ii) aconfidence interval for mean AUC_(0-infinity) between about 70% andabout 143%; (iii) a confidence interval for mean C_(max) between about70% and about 143%; (iv) a confidence interval for mean T_(max) betweenabout 70% and about 143%; or combinations thereof.

Element 20: A pharmaceutical composition as described herein, whereinthe percentage loading of the lurasidone in the solid dispersion is fromabout 10% (w/w) to about 80% (w/w), preferably from about 20% (w/w) toabout 70% (w/w), or from about 30% (w/w) to about 60% (w/w).

Element 21: A pharmaceutical composition as described herein, whereinthe weight ratio of the lurasidone in the solid dispersion to thepharmaceutically acceptable carrier in the solid dispersion is fromabout 1:1 to about 1:10, preferably from about 1:3 to about 1:5.

Element 22: A method for reducing the food effect exhibited bylurasidone following administration to a subject, said method comprisingadministration of a unit dosage form comprising a pharmaceuticalcomposition as described herein.

Element 23: A method for preparing a pharmaceutical composition asdescribed herein, which comprises preparing a mixture (e.g., a liquidmixture) or a solution including lurasidone or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier(e.g., a matrix polymer); and spray drying the mixture or the solutionto form a solid dispersion (e.g., a spray dried dispersion).

Element 24: A method for preparing a pharmaceutical composition asdescribed herein, which comprises preparing a mixture of lurasidone or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier; heating (e.g., up to or above the transition glasstemperature or melting temperature of the matrix polymer) the mixture toform a homogenous molten mass; extruding the molten mass; and coolingthe molten mass to form a solid dispersion (e.g., a hot melt extrusion).

Element 25: A pharmaceutical composition as described herein, whereinfollowing administration of said pharmaceutical composition to subjects,the ratio of the mean bioavailability for fed subjects to the meanbioavailability for fasted subjects is from about 1.0 to about 2.0.

Element 26: A pharmaceutical composition as described herein, whereinfollowing administration of said pharmaceutical composition to subjectsin fasted state, the mean bioavailability is greater than 20% in fastedstate.

Element 27: A pharmaceutical composition as described herein, whereinadministration of said pharmaceutical composition to fed and fastedsubjects produces a coefficient of variation in C_(max) of less thanabout 60%; or wherein administration of said pharmaceutical compositionto fasted subjects produces a coefficient of variation in C_(max) ofless than about 65%; or wherein administration of said pharmaceuticalcomposition to fed subjects produces a coefficient of variation inC_(max) of less than about 65%.

Element 28: A pharmaceutical composition as described herein, whereinadministration of said pharmaceutical composition to fed and fastedsubjects produces a coefficient of variation in AUC_(∞) of less thanabout 60%; or wherein administration of said pharmaceutical compositionto fasted subjects produces a coefficient of variation in AUC_(∞) ofless than about 65%; or wherein administration of said pharmaceuticalcomposition to fed subjects produces a coefficient of variation inAUC_(∞) of less than about 65%.

By way of non-limiting example, exemplary combinations applicable to theembodiments described in this application may include any combinationwith one or more of Elements 1-28, described above.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is the Powder X-Ray Diffraction (PXRD) pattern of the soliddispersion composition corresponding to extrudate 1 in Composition 1 (inExample 1).

FIG. 2 is the PXRD pattern of the solid dispersion compositioncorresponding to extrudate 2 in Composition 1 (in Example 1).

FIG. 3 shows the Powder X-Ray Diffraction (PXRD) pattern of thelurasidone solid dispersion in composition 2 (in Example 2).

FIG. 4 illustrates comparative dissolution profiles graph of LATUDA®tablet and composition 2 in 0.01N HCl followed by FaSSIF media at pH6.5.

FIG. 5 illustrates comparative dissolution profiles graph of LATUDA®tablet and composition 2 in 0.01N HCl followed by FeSSIF media at pH5.0.

FIG. 6 illustrates comparative dissolution profiles graph of LATUDA®tablet and compositions 1, 3 and 4 in 0.01N HCl followed by FaSSIF mediaat pH 6.5.

FIG. 7 illustrates comparative dissolution profiles graph of LATUDA®tablet and composition 1 in 0.01N HCl followed by FeSSIF media at pH5.0.

FIG. 8 illustrates comparative dissolution profiles graph of LATUDA®tablet and compositions 1, 3 and 4 in Mcillvaine buffer at pH 6.5.

FIG. 9 illustrates comparative dissolution profiles graph of LATUDA®tablet and compositions 1, 3 and 4 in FaSSIF media at pH 6.5.

FIG. 10 illustrates comparative dissolution profiles graph of LATUDA®tablet and compositions 1 and 2 in 0.1 N HCl.

FIG. 11 illustrates comparative dissolution profiles graph of LATUDA®tablet and compositions 1 and 2 in acetate buffer at pH 4.5.

DETAILED DESCRIPTION OF THE INVENTION

Pharmaceutical compositions according to the invention may improve theabsorption of lurasidone in the human body, and increase the absorptionand bioavailability of the drug in comparison to the commerciallyavailable oral formulations.

Unless defined otherwise, all the technical and scientific terms usedherein have the same meanings as commonly known by a person skilled inthe art. In the case that there is a plurality of definitions for theterms herein, the definitions provided herein will prevail.

As used herein the term “lurasidone” refers to lurasidone free base or apharmaceutically acceptable salt, solvate or hydrate thereof. In certainaspects, lurasidone free base or lurasidone hydrochloride may be used.Any crystalline form of lurasidone as well as the amorphous form may beused for the preparation of the pharmaceutical compositions of thepresent invention. In a preferred embodiment, lurasidone in amorphousform is used. In a preferred embodiment, the solid dispersions oflurasidone comprise the amorphous form of lurasidone.

The term “pharmaceutically acceptable” includes those substances, which,according to a common medical judgment, are suitable to be in contactwith a tissue of a patient without any inappropriate toxicity,irritation, allergic response, etc., have a reasonable balance betweenadvantages and disadvantages, and can be applied to its target useeffectively.

The terms “pharmaceutical composition,” “pharmaceutical product,”“pharmaceutical dosage form,” “dosage form,” “pharmaceuticalformulation,” etc., refer to a pharmaceutical composition that may beadministered to a patient in need of treatment, which may be in anyconventional formulation, e.g., in the form of a powder, a granule, apill, a capsule, a tablet, a solution, a suspension, or a patch, etc.

By “solid dispersion” is meant a molecular dispersion of a compound,particularly a drug substance within a polymer or carrier. The termsolid dispersion in general means a system in solid state comprising atleast two components, wherein one component is dispersed substantiallyevenly throughout the other component(s). For example, solid dispersionsmay be the dispersion of one or more active ingredients in an inertcarrier or matrix at solid state, prepared by the melting, solvent, ormelting-solvent methods. While not wishing to be bound by theory, in asolid dispersion, the drug may be present in a molecular state,colloidal state, metastable state, or an amorphous state. Formation of amolecular dispersion may provide a means of reducing the particle sizeto nearly molecular levels (i.e., there are no particles). As thepolymer dissolves, the drug is exposed to the dissolution media as fineparticles, which are amorphous, and which can dissolve and be absorbedmore rapidly than larger particles.

In certain aspects, the solid dispersions comprise an amorphouslurasidone drug substance and at least one or more polymers or carriers.By “amorphous drug substance,” is meant that the amorphous solidcontains drug substance in a substantially amorphous solid-state form,e.g., at least about 80% of the drug substance in the dispersion is inan amorphous form, more preferably at least about 90% of the drugsubstance in the dispersion is in an amorphous form, and most preferablyat least about 95% of the drug substance in the dispersion is inamorphous form.

The term “bioavailability” indicates the extent to which a drug oranother substance is utilized by a target tissue after administration.For example, “bioavailability” may refer to the fraction of drugabsorbed following administration to a subject or patient under a fastedstate. In certain aspects, under fasted state, the bioavailability oflurasidone when formulated as described herein is at least about 15%,but may be greater than 20%, 25%, 30%, 35%, 40%, 45%, or 50% of the doseadministered. As used herein, the term “improved bioavailability” refersto the increase in concentration of a drug in the body fluid provided bythe compositions of the present invention in the fasted state.

The term “in vivo” in general means in the living body of a plant oranimal, whereas the term “in vitro” generally means outside the body andin an artificial environment.

By “coefficient of variation” is meant the arithmetic standard deviationdivided by the arithmetic mean for a particular pharmacokineticparameter, where the data is obtained from a pharmacokinetic studyinvolving 10, 12, or more subjects or patients.

By “mean” is meant the arithmetic mean for a particular pharmacokineticparameter, where the data is obtained from a pharmacokinetic studyinvolving 10, 12, or more subjects or patients.

The term “peak plasma drug concentration (C_(max))” means the maximumplasma drug concentration attained after drug administration, e.g., themean peak concentration of a drug achieved in plasma after dosing.

The term “peak time of plasma drug concentration (T_(max))” means thetime when peak plasma drug concentration (C_(max)) is attained afterdrug administration.

The terms “AUC_(0-infin),” “AUC_(∞),” “AUC_(0-∞),” or “Area Under theCurve_(∞)”, means the area under a plasma drug concentration-time curvefrom time point of 0 to infinity after drug administration, e.g., themean integrated area under the curve for the plasma concentration of adrug, versus time from t=0 to ∞ following dosing. The term “AUC_(0-t)”means the area under a plasma drug concentration-time curve from timepoint of 0 to t after drug administration.

Certain embodiments relate to pharmaceuticals compositions as describedherein, which are stable, e.g., stable over the shelf life of the drugproduct. As used herein, the term “stable” is defined as no more thanabout 5% loss of lurasidone under typical commercial storage conditions.In certain embodiments, the formulations of the present invention willhave no more than about 3% loss of lurasidone, more preferably, no morethan about 2% loss of lurasidone, under typical commercial storageconditions. The composition retains at least about 95% of the potency oflurasidone after storing the composition at 40° C. and 75% relativehumidity for at least three months. In certain aspects, the term“stable” refers to chemical stability, wherein not more than 1.5% w/w oftotal related substances are formed on storage at accelerated conditionsof stability at 40° C. and 75% relative humidity or at 25° C. and 60%relative humidity for a period of at least three months or to the extentnecessary for use of the composition.

Reference throughout this specification will be made to theadministration of a pharmaceutical composition under fed or fastedconditions. It is well understood in the art that the pharmacokineticperformance of some compositions is affected by the presence or absenceof food in the gastro-intestinal system, which is referred to in the artas “fed” or “fasted” states.

For example, the term “fasted state” means that the human or othermammal has not ingested 500 calories or more than 500 calories for atleast two hours before taking the lurasidone solid oral dosage form andfor at least two hours after taking the lurasidone solid oral dosageform.

As used herein, the term “fed state” refers to a human or other mammalwho has eaten within about 30 minutes prior to drug administration. Forexample, the human or other mammal may have consumed at least 350calories, or consumed an United States Food and Drug Administration(FDA) standard high fat breakfast (or other meal containing a comparablequantity of fat and calories) within said time period, which is high inboth fat (approximately 50% of total calorie content of the meal) andcalories (approximately 800-1000 calories) within about 30 minutes priorto drug administration.

The term “food effect” as used herein means food-drug interactions whicheither decrease or increase the extent of drug absorption. In otherwords the bioavailability for a drug is altered when administered underfasted state, in comparison to the drug when administered in the fedstate. It may refer to a relative difference in one or more of AUC_(∞),AUC_(0-t), C_(max), and/or T_(max) of a drug, when said drug or aformulation thereof is administered orally to a human, concomitantlywith food or in a fed state as compared to the same values when the sameformulation is administered in a fasted state or without food.

In one aspect, the pharmaceutical compositions described herein reduceor eliminate the food effect. As used herein, “reducing the food effect”refers to narrowing the difference in bioavailability, e.g., AUC_(∞),AUC_(0-t), C_(max), and/or T_(max), for a drug administered under fastedstates in comparison to the drug administered under fed states. Incertain aspects, the food effect is eliminated. Thus, upon oraladministration of a pharmaceutical composition as described herein, to amammal in need thereof, there is not a significant adverse food effect.In other words, the difference between a pharmacokinetic parametermeasured after oral administration to a mammal with and without food,respectively, is less than 40%, e.g., less than 35%, less than 30%, lessthan 25%, less than 20%, less than 15%, less than 10 or less than 5%.

In other embodiments, the dose of lurasidone is at the most about 98%w/w, or at the most about 95% w/w, or at the most about 90% w/w, or atthe most about 85% w/w, or at the most about 80% w/w, or at the mostabout 75% w/w, or at the most about 70% w/w, or at the most about 65%w/w, or at the most about 60% w/w, or at the most about 55% w/w or atthe most about 50% w/w of the dose of the lurasidone administered in theform of a commercially available product.

Pharmacokinetic parameters for the compositions can be measured in asingle or multiple dose study using a replicate or a nonreplicatedesign. For example, the pharmacokinetic parameters can be measured in asingle dose pharmacokinetic study using a two-period, two-sequencecrossover design. Alternately, a four-period, replicate design crossoverstudy may also be used. Pharmacokinetic parameters characterizing rateand extent of lurasidone absorption are evaluated statistically. Thearea under the plasma concentration-time curve from time zero to thetime of measurement of the last quantifiable concentration (AUC_(0-t))and to infinity (AUC_(0-infinity)), C_(max), and T_(max) can bedetermined according to standard techniques. Statistical analysis ofpharmacokinetic data is performed on logarithmic transformed data (e.g.,AUC_(0-t), AUC_(0-infinity), or C_(max) data) using analysis of variance(ANOVA).

The difference in AUC of the compositions of the present invention, whenadministered in the fed versus the fasted state, preferably is less thanabout 100%, less than about 90%, less than about 80%, less than about70%, less than about 65%, less than about 60%, less than about 55%, lessthan about 50%, less than about 45%, less than about 40%, less thanabout 35%, less than about 30%, less than about 25%, less than about20%, less than about 15%, less than about 10%, less than about 5%, orless than about 3%.

The difference in C_(max) of the compositions of the present invention,when administered in fed versus the fasted state, preferably is lessthan about 100%, less than about 90%, less than about 80%, less thanabout 70%, less than about 65%, less than about 60%, less than about55%, less than about 50%, less than about 45%, less than about 40%, lessthan about 35%, less than about 30%, less than about 25%, less thanabout 20%, less than about 15%, less than about 10%, less than about 5%,or less than about 3%.

In some aspects, following administration of the pharmaceuticalcomposition to subjects (e.g., fed subjects or fasted subjects), themean bioavailability is greater than about 20% (e.g., greater than 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, oreven 99%) or between about 20% to about 90% (e.g., from 20% to 30%, from20% to 40%, from 20% to 50%, from 20% to 60%, from 20% to 70%, from 20%to 80%, from 20% to 90%, from 30% to 40%, from 30% to 50%, from 30% to60%, from 30% to 70%, from 30% to 80%, from 30% to 90%, from 40% to 50%,from 40% to 60%, from 40% to 70%, from 40% to 80%, from 40% to 90%, from50% to 60%, from 50% to 70%, from 50% to 80%, from 50% to 90%, from 60%to 70%, from 60% to 80%, from 60% to 90%, from 70% to 80%, from 70% to90%, and from 80% to 90%).

In some aspects, the ratio of the mean bioavailability for fed subjectsto the mean bioavailability for fasted subjects is from about 1.0 toabout 2.0 (e.g., from 1.0 to 1.1, from 1.0 to 1.2, from 1.0 to 1.3, from1.0 to 1.4, from 1.0 to 1.5, from 1.0 to 1.6, from 1.0 to 1.7, from 1.0to 1.8, from 1.0 to 1.9, from 1.3 to 1.4, from 1.3 to 1.5, from 1.3 to1.6, from 1.3 to 1.7, from 1.3 to 1.8, from 1.3 to 1.9, from 1.3 to 2.0,from 1.5 to 1.6, from 1.5 to 1.7, from 1.5 to 1.8, from 1.5 to 1.9, from1.5 to 2.0, from 1.7 to 1.8, from 1.7 to 1.9, from 1.7 to 2.0, from 1.8to 1.9, and from 1.8 to 2.0).

In some aspects, administration of the pharmaceutical composition to fedand fasted subjects produces a coefficient of variation in AUC_(0-t),T_(max), C_(max) and/or AUC_(∞) of less than about 60% (e.g., less than55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, and 15%). In particularembodiments, the coefficient of variation in C_(max) and/or AUC_(∞) isof from about 20% to about 60% (e.g., from 20% to 30%, from 20% to 35%,from 20% to 40%, from 20% to 45%, from 20% to 50%, from 20% to 55%, from30% to 35%, from 30% to 40%, from 30% to 45%, from 30% to 50%, from 30%to 55%, from 30% to 60%, from 35% to 40%, from 35% to 45%, from 35% to50%, from 35% to 55%, from 35% to 60%, from 40% to 45%, from 40% to 50%,from 40% to 55%, from 40% to 60%, from 45% to 50%, from 45% to 55%, from45% to 60%, from 50% to 55%, from 50% to 60%, and from 55% to 60%).

In some aspects, administration of the pharmaceutical composition to afasted subject produces mean C_(max) that is greater than about 50 ng/mL(e.g., greater than about 60 ng/mL, 70 ng/mL, 80 ng/mL, 90 ng/mL, 100ng/mL, 110 ng/mL, 120 ng/mL, 130 ng/mL, 140 ng/mL, 150 ng/mL, 200 ng/mL,250 ng/mL, and/or up to about 300 ng/mL) for a 40 mg eq. dose oflurasidone hydrochloride.

In some aspects, administration of the pharmaceutical composition to afasted subject produces mean AUC_(0-∞) that is greater than about 200hr*ng/mL (e.g., greater than 250 hr*ng/mL, 300 hr*ng/mL, 350 hr*ng/mL,400 hr*ng/mL, 450 hr*ng/mL, 500 hr*ng/mL, 550 hr*ng/mL and/or greaterthan about 600 hr*ng/mL) for a 40 mg eq. dose of lurasidonehydrochloride.

Methods for Making Solid Dispersions

The present application relates to pharmaceutical compositionscomprising lurasidone solid dispersion and pharmaceutically acceptableexcipients. In an embodiment, lurasidone solid dispersion of the presentapplication comprises lurasidone and a pharmaceutically acceptablepolymer. In an embodiment, lurasidone solid dispersion of the presentapplication comprises crystalline or amorphous forms of lurasidone freebase or lurasidone hydrochloride and a pharmaceutically acceptablepolymer.

The solid dispersion composition comprising lurasidone may be formed byany conventional technique, e.g., spray drying, co-grinding, hot meltextrusion, freeze drying, rotary evaporation, solvent evaporation,co-precipitation, lyophilization, or any suitable solvent removalprocess.

The solid dispersions consist of two or more components, generally apharmaceutically acceptable carrier (e.g., a polymer), and drug.Optionally, other pharmaceutically acceptable excipients may beincluded, such as a solubilizer, a surfactant and/or other additives.While not wishing to be bound by theory, the pharmaceutically acceptablecarrier in the solid dispersion may reduce the molecular mobility of thedrug to avoid the phase separation and re-crystallization of drug duringstorage. Thus, the resulting solid dispersions may have increasedsolubility. In certain aspects, the increase in solubility of the drugin solid dispersion is mainly because drug remains in amorphous formwhich is associated with a higher energy state as compared tocrystalline counterpart and due to that it requires very less externalenergy to dissolve.

In some embodiments, at least about 90% (e.g., at least 95%, 96%, 97%,98%, 99%, 99.5%, or even 99.9%, such as from 90% to 99.9%, from 90% to99.5%, from 90% to 99%, from 90% to 98%, from 90% to 97%, from 90% to96%, from 90% to 95%, from 95% to 99.9%, from 95% to 99.5%, from 95% to99%, from 95% to 98%, from 95% to 97%, and from 95% to 96%) of thelurasidone is in amorphous form.

In an embodiment, lurasidone solid dispersion of the present applicationcomprises lurasidone and a pharmaceutically acceptable polymer, whereinthe pharmaceutically acceptable polymer is selected from the groupconsisting of hydroxypropyl methyl cellulose acetate succinate(HPMC-AS), polyvinyl pyrrolidine vinyl acetate (PVP/VA) copolymer,hydroxypropyl methylcellulose phthalate (HPMCP) and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer(PCL-PVAc-PEG).

In some aspects, the pharmaceutical composition includes a soliddispersion of the lurasidone or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier (e.g., apharmaceutically acceptable polymer), where the weight ratio of thelurasidone or a pharmaceutically acceptable salt thereof, to thepharmaceutically acceptable carrier is from about 1:6 to about 1:1.5(e.g., from 1:6 to 1:2, from 1:6 to 1:2.5, from 1:6 to 1:3, from 1:6 to1:3.5, from 1:6 to 1:4, from 1:6 to 1:4.5, from 1:6 to 1:5, from 1:5 to1:2, from 1:5 to 1:2.5, from 1:5 to 1:3, from 1:5 to 1:3.5, from 1:5 to1:4, from 1:5 to 1:4.5, from 1:5 to 1:1.5, from 1:4 to 1:1.5, from 1:4to 1:2, from 1:4 to 1:2.5, from 1:4 to 1:3, from 1:4 to 1:3.5, from 1:3to 1:1.5, from 1:3 to 1:2, from 1:3 to 1:2.5, and from 1:2 to 1:1.5).

In an embodiment, a lurasidone solid dispersion of the presentapplication comprises lurasidone and a pharmaceutically acceptablepolymer, wherein lurasidone and polymer are in the ratio of about 1:1 toabout 1:4 (w/w).

In an embodiment, a lurasidone solid dispersion of the presentapplication comprises lurasidone and a pharmaceutically acceptablepolymer, wherein lurasidone is lurasidone free base and the polymer isHPMC-AS. More specifically, lurasidone free base and HPMC-AS are in theratio of about 1:1 to about 1:4 (w/w), preferably in the ratio of about1:3 (w/w).

In an embodiment, a lurasidone solid dispersion of the presentapplication comprises lurasidone and a pharmaceutically acceptablepolymer, wherein lurasidone is lurasidone free base and the polymer isPVP/VA copolymer. More specifically, lurasidone free base and PVP/VA arein the ratio of about 1:1 to about 1:4 (w/w), preferably in the ratio ofabout 1:3 (w/w).

In an embodiment, a lurasidone solid dispersion of the presentapplication comprises lurasidone and a pharmaceutically acceptablepolymer, wherein lurasidone is lurasidone free base and the polymer isHPMCP. More specifically, lurasidone free base and HPMCP are in theratio of about 1:1 to about 1:4 (w/w), preferably in the ratio of about1:3 (w/w).

In an embodiment, a lurasidone solid dispersion of the presentapplication comprises lurasidone and a pharmaceutically acceptablepolymer, wherein lurasidone is lurasidone free base and the polymermixture which is a mixture of HPMC-AS and PVP/VA in the ratio of 1:1.More specifically, lurasidone free base and HPMC-AS and PVP/VA polymermixture are in the ratio of about 1:1 to about 1:4 (w/w), preferably inthe ratio of about 1:3 (w/w).

The solid dispersions of the present invention may include one or moresolubilizers, i.e., additives which increase solubility of thepharmaceutical active ingredient in the solid dispersion or additiveswhich act as pore-forming agents in the solid dispersion. Suitablesolubilizers for use in compositions of the present invention includesorbitol, mannitol, transcutol, polyvinylalcohol, hydroxypropylmethylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone,glycofurol and transcutol. The concentration of solubilizer ranges fromabout 1% to about 30% w/w of polymer concentration.

The solid dispersions of the present invention optionally may includeone or more surfactants. Surfactants are compounds which are capable ofimproving the wetting of the drug and/or enhancing the dissolution. Thesurfactants can be selected from hydrophilic surfactants or lipophilicsurfactants or mixtures thereof. The surfactants can be anionic,nonionic, cationic, and zwitterionic surfactants. Surfactants accordingto the present invention include, but not limited to, polyoxyethylenealkylaryl ethers such as polyoxyethylene lauryl ether, polyoxyethylenecetyl ether, polyoxyethylene stearyl ether; polyethylene glycol fattyacid esters such as PEG monolaurate, PEG dilaurate, PEG distearate, PEGdioleate; polyoxyethylene sorbitan fatty acid ester such as polysorbate40, polysorbate 60, polysorbate 80; sorbitan fatty acid mono esters suchas sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate,sorbitan trioleate, sodium lauryl sulfate, sodium dioctyl sulfosuccinate(DOSS), lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol,polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides,cremophor RH 40, and the like or combinations thereof. The concentrationof surfactant ranges from about 1% to about 10% w/w of polymerconcentration.

The lurasidone starting material used in the process for preparation ofthe solid dispersion may be in any crystalline form or amorphous form.Alternatively, it may be obtained in situ from a previous processingstep.

The lurasidone in the solid dispersion obtained may be present in eithercrystalline or amorphous powder form.

In some aspects herein, the percentage loading of lurasidone in thesolid dispersion is from about 1% to about 90% (w/w) (e.g., from 1% to19%, from 10% to 19%, from 10% to 20%, from 10% to 30%, from 10% to 40%,from 10% to 50%, from 10% to 60%, from 10% to 70%, from 10% to 80%, from10% to 90%, from 20% to 30%, from 20% to 40%, from 20% to 50%, from 20%to 60%, from 20% to 70%, from 20% to 80%, from 20% to 90%, from 21% to30%, from 21% to 34%, from 21% to 40%, from 21% to 50%, from 21% to 60%,from 21% to 70%, from 21% to 80%, from 21% to 90%, from 30% to 40%, from30% to 50%, from 30% to 60%, from 30% to 70%, from 30% to 80%, from 30%to 90%, from 36% to 40%, from 36% to 49%, from 36% to 60%, from 36% to70%, from 36% to 80%, from 36% to 90%, from 40% to 50%, from 40% to 60%,from 40% to 70%, from 40% to 80%, from 40% to 90%, from 50% to 60%, from50% to 70%, from 50% to 80%, from 50% to 90%, 51% to 60%, from 51% to70%, from 51% to 80%, from 51% to 90%, from 60% to 70%, from 60% to 80%,from 60% to 90%, from 70% to 80%, and from 70% to 90%). In somepreferred embodiments, the percentage loading of lurasidone is fromabout 10% to about 60% (w/w) (e.g., from 10% to 20%, from 10% to 30%,from 10% to 40%, from 10% to 50%, from 10% to 60%, from 20% to 30%, from20% to 40%, from 20% to 50%, from 20% to 60%, from 30% to 40%, from 30%to 50%, from 30% to 60%, from 40% to 50%, and from 40% to 60%).

In an aspect, methods are provided for preparing a pharmaceuticalcomposition as described herein, which comprise preparing a mixture(e.g., a liquid mixture) or a solution including lurasidone or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier (e.g., a matrix polymer); and spray drying themixture or the solution to form a solid dispersion (e.g., a spray drieddispersion).

In an aspect, methods are provided for preparing a pharmaceuticalcomposition as described herein, which comprise preparing a mixture oflurasidone or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier; heating (e.g., up to or above thetransition glass temperature or melting temperature of the matrixpolymer) the mixture to form a homogenous molten mass; extruding themolten mass; and cooling the molten mass to form a solid dispersion(e.g., a hot melt extrusion).

The resultant solid dispersions can be blended with one or moreexcipients, as described herein, and then granulated and/or compacted toproduce a final blend for encapsulating or tableting. In particularembodiments, the solid dispersion may be combined with one or moreexcipient(s) may be included to form granules, e.g., such as a bindingagent, a filler, a disintegrating agent, a wetting agent, a glidant, anda lubricant.

Spray Drying Process

In certain aspects, the solid dispersions are made by spray drying.Generally, one or more pharmaceutically acceptable carrier(s) andlurasidone are combined either with or without solvent(s) to form amixture or a solution, which can be spray-dried to form a soliddispersion. For example, in a typical spray drying technique, the soliddispersion is formed by dispersing or dissolving the drug and a polymerin a suitable solvent, and subsequently spray drying to form the soliddispersion in the form of a powder.

Any suitable solvent may be used for spray drying. Examples of suitablesolvents or dispersion media include but are not limited to: methylenechloride, chloroform, ethanol, methanol, propan-2-ol, ethyl acetate,acetone, water, or mixtures thereof.

In certain aspects, the solution may have about 4% (w/w) to about 15%(w/w) of total solids. Percentage (w/w) total solids is determined bydividing the total mass of the compound and one or more matrix polymersby the total mass of the compound, one or more matrix polymers, and oneor more solvents.

In particular embodiments, the SDD includes about 20% (w/w) oflurasidone, with the one or more pharmaceutically acceptable carrier(s),such as matrix polymers. Preferably, the weight ratio of lurasidone tothe one or more pharmaceutically acceptable carrier(s) is about 1:4.

For example, to produce a 20% (w/w) lurasidone in a SDD, a solution wasprepared having about 2% (w/w) lurasidone and about 8% (w/w) of apharmaceutically acceptable matrix polymer or a combination of apharmaceutically acceptable matrix polymer in acetone. The solution wasthen spray dried at the appropriate temperature (e.g., between about 95°C. and 110° C. for HPMC-AS at the appropriate solution flow rate).

The solution can be spray dried to form a spray-dried dispersion (SDD),which can optionally be further subjected to suitable drying steps.Optionally, other excipients may then be blended into the resultingsolid dispersions (with or without milling or grinding) to form acomposition suitable for use in dosage forms such as tablets andcapsules.

Hot Melt Extrusion Process

In certain aspects, the solid dispersions are made by hot melt extrusion(“HME”), e.g., a process whereby a composition is heated and/orcompressed to a molten (or softened) state and subsequently forcedthrough an orifice in a die where the extruded product is formed intoits final shape in which it solidifies upon cooling. Hot melt extrusionis simple and easy to operate, and decreases energy consumption, andincreases productivity.

In the HME process, a blend is conveyed through one or more heatingzones typically by a screw mechanism. The screw or screws are rotated bya variable speed motor inside a cylindrical barrel where only a smallgap exists between the outside diameter of the screw and the insidediameter of the barrel. In this conformation, high shear is created atthe barrel wall and between the screw fights by which the variouscomponents of the powder blend are well mixed and disaggregated. The diecan be a dual manifold, multi-manifold or feed-block style die. As usedherein, the term extrudate refers to hot-melt extruded composition.

In an embodiment, lurasidone solid dispersion of the present applicationis obtained by hot melt extrusion. A physical mixture of lurasidone baseand polymer was subjected to hot melt extrusion at 70-180° C. through ahot melt extruder (such as omicron 10P) having the same directionrotation type twin screws. The obtained hot-melt extrusion product waschilled, milled and passed through a 30-mesh screen.

In other embodiments, the mixture can then be fed into a pre-heatedextruder (e.g., an extruder having temperature zones between about 70°C. to about 180° C.) to produce an initial extrudate.

Preferably, the hot-melt extrusion is to be carried out at a temperaturethat allows the dissolution of the lurasidone used as staring materialwithin the mixture of pharmaceutically acceptable excipients, e.g., anenteric polymer and/or a non-enteric polymer. In certain embodiments,the pharmaceutically acceptable carrier(s) and lurasidone can be heatednear or past the glass transition temperature Tg or melting temperatureTm to form a liquid mixture. After the mixture is heated to form ahomogenous molten mass, it may be extruded and cooled to form a soliddispersion.

The temperature and screw speed of the hot melt extruder are selectedbased on the type of pharmaceutically acceptable carrier employed, e.g.,to extrude the target mixture smoothly, wherein the extrusion speed andthe yield can meet the requirements, and the solubilization effect isgood.

In certain aspects, optionally, a surfactant or solubilizer may also beincluded in the mixture to enhance dissolution and/or enhance stability.An exemplary surfactant includes sodium lauryl sulfate, in any useful oreffective amount (e.g., from about 1% to about 10% (w/w), e.g., about 5%(w/w)).

The extrudates can optionally be pelletized or milled to form a soliddispersion amenable for further processing in a suitable unit dosageform. In certain aspects, the extrudate is then pelletized and milled(e.g., to a size less than about 500 μm) to produce a milled extrudate.The milled/pelletized extrudate can be sieved and blended with variouspharmaceutically acceptable excipients, where the resultant blend wasthen co-milled. The co-milled blend can be further processed by adding alubricant (e.g., magnesium stearate), and the resultant, processed blendcan be used to fill a unit dosage form (e.g., capsule).

Pharmaceutical Compositions Comprising Lurasidone Solid Dispersions

The solid dispersion may be used for filling any one of the unit dosageforms described herein (e.g., a capsule) or for tableting. The soliddispersion can optionally be further processed before filling ortableting. Exemplary further processing includes spheronizing,pelletizing, milling, injection molding, sieving, and/or calendering thesolid dispersion.

Amorphous solid dispersions of lurasidone of the present application canbe optionally subjected to a particle size reduction procedure before orafter the completion of drying of the product to produce desiredparticle sizes and distributions. Milling or micronization can beperformed to achieve the desired particle sizes or distributions.Equipment that may be used for particle size reduction include, withoutlimitation thereto, ball mills, roller mills, hammer mills, and jetmills.

In another general aspect, there is provided amorphous form oflurasidone solid dispersion comprising amorphous form of lurasidonehaving particle size distributions wherein D90 is less than about 500microns or less than about 200 microns or less than about 100 microns orless than about 50 microns or less than about 40 microns or less thanabout 30 microns or less than about 20 microns or less than about 10microns or any other suitable particle sizes.

The lurasidone solid dispersion may be combined with pharmaceuticallyacceptable excipients to make other pharmaceutical compositions, or afinished dosage form. The one or more additional pharmaceuticallyacceptable excipients are selected from diluents, binders,disintegrants, fillers, lubricants, glidants, surfactants, stabilizingagents, antioxidants, alkaline stabilizers, colors, flavors,preservatives, and combinations thereof.

In an embodiment, pharmaceutical compositions comprising lurasidonesolid dispersion and pharmaceutically acceptable excipients are preparedby using, but not limited, to wet granulation, dry granulation, anddirect compression.

In an embodiment, pharmaceutical compositions comprising lurasidonesolid dispersion and pharmaceutically acceptable excipients are preparedby using direct compression, which process comprises mixing lurasidonesolid dispersion and pharmaceutically acceptable excipients, theresultant mixture is either compressed to tablet or filled in hardgelatin capsules.

In an embodiment, pharmaceutical compositions comprising lurasidonesolid dispersion and pharmaceutically acceptable excipients are preparedby using dry granulation, wherein dry granulation is carried out byeither direct compaction or roller compaction or both.

In an embodiment, pharmaceutical compositions comprising lurasidonesolid dispersion and pharmaceutically acceptable excipients are preparedby using direct compaction dry granulation, which process comprisescompressing mixture of lurasidone solid dispersion and intragranularmaterial into slug, compressed slugs are milled and passed through messscreen manually or automatically which results in granules. Theresulting granules were mixed with extra granular material. This finalmixture is either compressed to tablet or filled in hard gelatincapsules.

In an embodiment, pharmaceutical compositions comprising lurasidonesolid dispersion and pharmaceutically acceptable excipients are preparedby using roller compaction dry granulation, which process comprisespassing a mixture of lurasidone solid dispersion and intragranularmaterial between two high-pressure rollers to form consolidated anddensified material, the resultant densified material is then reduced toa uniform granule size by milling, which were then mixed with extragranular material. This final mixture is either compressed to tablet orfilled in hard gelatin capsules.

In an embodiment, pharmaceutical compositions comprising lurasidonesolid dispersion and pharmaceutically acceptable excipients are preparedby wet granulation, which process comprises: (a) mixing lurasidone soliddispersion and pharmaceutically acceptable excipients (b) addingsufficient solvent, wherein the solvent is selected form water,isopropanol, ethanol, to the mixture obtained from step (a) under shearto generate granules; (c) milling or grinding the granules followed bysieving of said granules; optionally mixing with other excipients. Thisfinal mixture is either compressed to tablet or filled in hard gelatincapsules.

The pharmaceutical compositions of the present invention include one ormore diluents. In an embodiment, suitable diluents includemicrocrystalline cellulose, calcium carbonate, calciumphosphate-dibasic, calcium phosphate-tribasic, calcium sulfate,cellulose powdered, dextrates, dextrins, dextrose excipients, fructose,kaolin, lactitol, lactose, mannitol, sorbitol, starch, starchpregelatinized, sucrose, sugar compressible, sugar confectioners and thelike.

In an embodiment, diluent is included either in intragranular materialor extra granular material or both.

In an embodiment, the concentration of diluent ranges from about 35% toabout 60% w/w of total composition.

In an embodiment, the diluent concentration in the intragranularmaterial ranges from about 10% to about 60% w/w of total composition,preferably about 25% to about 35%, more preferably about 27% w/w.

In an embodiment, the diluent concentration in the extra granularmaterial ranges from about 10% to about 60% w/w of total composition,preferably about 25% to about 35%, more preferably about 28% w/w.

In an embodiment, suitable binders include methyl cellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, microcrystalline cellulose, gelatin, gum arabic, ethylcellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar,tragacanth, sodium alginate, propylene glycol and the like.

In an embodiment, the binder concentration ranges from about 10% toabout 60% w/w of total composition, preferably about 25% to about 35%w/w.

In an embodiment, suitable disintegrating agents include croscarmellosesodium, low-substituted hydroxypropyl cellulose (L-HPC), sodium starchglycollate, carboxymethyl cellulose, calcium carboxymethyl cellulose,sodium carboxymethyl cellulose, starch, crystalline cellulose,hydroxypropyl starch, pregelatinized starch, and the like and mixturesthereof.

In an embodiment, the disintegrating agent concentration ranges fromabout 1% to about 10% w/w of total composition.

In an embodiment, suitable lubricants/glidants include colloidal silicondioxide, stearic acid, magnesium stearate, calcium stearate, talc,hydrogenated castor oil, sucrose esters of fatty acid, microcrystallinewax, yellow beeswax, white beeswax, and the like and mixtures thereof.

In an embodiment, the lubricants/glidants concentration ranges fromabout 0.5% to about 5% w/w of total composition.

In an embodiment, suitable coloring agent include dyes and pigments suchas iron oxide red or yellow, titanium dioxide, talc.

In an embodiment, the coloring agent concentration ranges from about0.1% to about 1% w/w of total composition.

Solid dispersion technique is useful in improving bioavailability byincreasing solubility. There are various methods which are used forpreparing a solid dispersion like solvent evaporation method, meltingmethod and spray drying method. Conversion of crystalline form ofpharmaceutical active ingredient to amorphous form when formulated intoa solid dispersion is one of the mechanisms responsible for improvedsolubility, which in turn improves bioavailability of formulation, andreduces the effect of food on dissolution of lurasidone.

In an embodiment, solid dispersion and tablets manufactured as per thepresent invention were tested for comparative dissolution by using USPapparatus-II (paddle) in 0.1N HCl followed by pH 6.8 phosphate bufferand McIlvaine buffer at pH 3.8 followed by pH 6.8.

In an embodiment, tablets manufactured as per the present invention weretested for comparative dissolution by using USP apparatus-II (paddle) in0.01N HCl followed by FaSSIF media at pH 6.5.

In an embodiment, tablets manufactured as per the present invention weretested for comparative dissolution by using USP apparatus-II (paddle) in0.01N HCl followed by FeSSIF media at pH 5.0.

In an embodiment, tablets manufactured as per the present invention weretested for comparative dissolution by using USP apparatus-II (paddle) inMcIlvaine buffer at pH 6.5.

In an embodiment, tablets manufactured as per the present invention weretested for comparative dissolution by using USP apparatus-II (paddle) inFaSSIF media at pH 6.5.

In an embodiment, tablets manufactured as per the present invention weretested for comparative dissolution by using USP apparatus-II (paddle) in0.1N HCl.

In an embodiment, tablets manufactured as per the present invention weretested for comparative dissolution by using USP apparatus-II (paddle) inacetate buffer at pH 4.5.

The 0.1N HCl acid dissolution media was prepared by adding 68 mL ofconcentrated hydrochloric acid to 8000 mL of water and mixing well. 675mL of resultant solution was used as acid media. Buffer media wasobtained by adding 225 mL of pH 6.8 phosphate-citrate buffer to the 675mL of acid media obtained above, mixed well and adjusted pH to 6.8 byusing the 2N sodium hydroxide solution or hydrochloric acid.

McIlvaine buffer acid media was prepared by mixing 600 mL of citric acidbuffer (0.025 molar) and 400 mL of disodium hydrogen phosphate buffer(0.05 molar), adjust the pH to 3.8 by using diluted ortho-phosphoricacid. 675 mL of the resultant solution was used as McIlvaine buffer acidmedia at pH 3.8. Buffer media at pH 6.8 was prepared by adding 225 mL ofpH 6.8 phosphate-citrate buffer to 675 mL of McIlvaine buffer acid mediaand adjusting pH to 6.8 with 2N NaOH or ortho-phosphoric acid.

In an embodiment, the present application relates to methods of usingpharmaceutical compositions of the present application for treatment ofschizophrenia, bipolar disorders or senile dementia.

The requirement of improved and/or more flexible compositions may be toobtain the same or better bioavailability than already seen from thecommercially available products.

In an embodiment, the present application provides a method of treatingCNS disorder in human, which method comprises administering to the humanin a fasted state, an oral dosage form comprising an amount oflurasidone effective to treat said CNS disorder, wherein the area underthe plasma concentration versus time curve (AUC_(0-inf)) of thelurasidone in the human subsequent to said administering is from 70% to143% of the mean area under the lurasidone plasma concentration versustime curve (AUC_(0-inf)) resulting from administration of a controllurasidone immediate release oral tablet containing the same amount oflurasidone to a cohort of humans in a fed state.

Dosage and Administration

The pharmaceutical compositions as described herein may be used inmethods of treatment, in which an effective amount of lurasidone or apharmaceutically acceptable salt thereof is administered to a patient.The pharmaceutical compositions described herein may be used to treatvarious CNS disorders, including but not limited to depression ordepressive episodes associated with biopolar I disorder (bipolardepression) in adults and pediatric patients, schizophrenia and/orsenile dementia. Senile dementia includes both Alzheimer's dementia andcerebrovascular dementia. In certain aspects, the pharmaceuticalcompositions described herein may be used to treat adults andadolescents (e.g., about 13-17 years). In certain aspects, thepharmaceutical compositions described herein may be used as monotherapyor as adjunctive therapy. For example, for treating bipolar depression,the pharmaceutical compositions described herein may be used inadjunctive therapy with lithium or valproate. In certain aspects,examples of conditions that may be treated or prevented by administeringpharmaceutical compositions as described herein include CNS or mentaldiseases, e.g., schizophrenia, bipolar I disorder, autism, bipolardisorder and depression.

For administration to animal or human subjects, the pharmaceuticalcompositions comprise an effective dosage amount of lurasidone or apharmaceutically acceptable salt thereof. The formulation may beprepared using conventional methods, for example, depending on thesubject to be treated, the mode of administration, and the type oftreatment desired (e.g., prevention, prophylaxis, or therapy).

The lurasidone or pharmaceutically acceptable salt thereof, may bepresent in amounts totaling 1-95% by weight of the total weight of thecomposition.

Preferably, the pharmaceutical composition will be provided in a dosageform that is suitable for oral administration, including but not limitedto hard capsules (e.g., hard gelatin capsules or hard hydroxypropylmethylcellulose capsules), soft gelatin capsules, tablets, caplets,enteric coated tablets, chewable tablets, enteric coated hard gelatincapsules, enteric coated soft gelatin capsules, minicapsules, lozenges,films, strips, gelcaps, dragees, suspensions, syrups, or sprinkles. Thecompositions may be formulated according to conventional pharmaceuticalpractice.

The dosage levels can be dependent on the nature of the condition, drugefficacy, the condition of the patient, the judgment of thepractitioner, and the frequency and mode of administration. The unitdosage forms can be administered to achieve any daily amount describedherein, such as by administering one to five times daily (e.g., one,two, three, four, or five times daily).

In an aspect, the invention relates to a pharmaceutical composition inunit dosage form for oral administration, the composition including fromabout 20 mg to about 160 mg (e.g., from 20 mg to 30 mg, from 20 mg to 40mg, from 20 mg to 50 mg, from 20 mg to 75 mg, from 20 mg to 100 mg, from20 mg to 125 mg, from 20 mg to 160 mg, from 30 mg to 40 mg, from 30 mgto 50 mg, from 30 mg to 75 mg, from 30 mg to 100 mg, from 30 mg to 125mg, from 30 mg to 160 mg, from 40 mg to 50 mg, from 40 mg to 75 mg, from40 mg to 100 mg, from 40 mg to 125 mg, from 40 mg to 160 mg, from 50 mgto 75 mg, from 50 mg to 100 mg, from 50 mg to 125 mg, from 50 mg to 160mg, from 60 mg to 75 mg, from 60 mg to 100 mg, from 60 mg to 125 mg,from 60 mg to 160 mg, from 70 mg to 75 mg, from 70 mg to 100 mg, from 70mg to 125 mg, from 70 mg to 160 mg, from 80 mg to 100 mg, from 80 mg to125 mg, from 80 mg to 160 mg, from 90 mg to 100 mg, from 90 mg to 125mg, from 90 mg to 160 mg, from 100 mg to 125 mg, or from 100 mg to 160mg) of lurasidone, or a pharmaceutically acceptable salt thereof (e.g.,lurasidone hydrochloride). Preferred dosage amounts include 20 mg, 40mg, 60 mg, 80 mg, or 120 mg of lurasidone hydrochloride, or 18.62 mg,37.24 mg, 55.87 mg, 74.49 mg or 111.74 mg of lurasidone free base.

In an aspect, the invention relates to certain methods of treatmentcomprising administration of a pharmaceutical composition describedherein, where the total daily dosage amount is from about 20 mg to about160 mg (e.g., from 20 mg to 30 mg, from 20 mg to 40 mg, from 20 mg to 50mg, from 20 mg to 75 mg, from 20 mg to 100 mg, from 20 mg to 125 mg,from 20 mg to 160 mg, from 30 mg to 40 mg, from 30 mg to 50 mg, from 30mg to 75 mg, from 30 mg to 100 mg, from 30 mg to 125 mg, from 30 mg to160 mg, from 40 mg to 50 mg, from 40 mg to 75 mg, from 40 mg to 100 mg,from 40 mg to 125 mg, from 40 mg to 160 mg, 50 mg to 75 mg, from 50 mgto 100 mg, from 50 mg to 125 mg, from 50 mg to 160 mg, from 60 mg to 75mg, from 60 mg to 100 mg, from 60 mg to 125 mg, from 60 mg to 160 mg,from 70 mg to 75 mg, from 70 mg to 100 mg, from 70 mg to 125 mg, from 70mg to 160 mg, from 80 mg to 100 mg, from 80 mg to 125 mg, from 80 mg to160 mg, from 90 mg to 100 mg, from 90 mg to 125 mg, from 90 mg to 160mg, from 100 mg to 125 mg or from 100 mg to 160 mg) of lurasidone, or apharmaceutically acceptable salt thereof (e.g., lurasidonehydrochloride). Preferred dosage amounts include 20 mg, 40 mg, 60 mg, 80mg, or 120 mg of lurasidone hydrochloride, or 18.62 mg, 37.24 mg, 55.87mg, 74.49 mg or 111.74 mg of lurasidone free base.

The term “unit dosage form” refers to a physically discrete unitsuitable as a unitary dosage, such as a tablet, caplet, hard capsule, orsoft capsule, each unit containing a predetermined quantity of a drug.

By “effective” amount is meant the amount of a drug sufficient to treat,prevent, or ameliorate a condition in a subject or patient. Theeffective amount of lurasidone or pharmaceutically acceptable saltthereof, used to practice the present invention for therapeuticmanagement of a condition may be determined and adjusted by a person ofordinary skill to provide the appropriate amount and dosage regimen,e.g., depending upon one or more of the manner of administration, theage, body weight, sex, and/or general health of the patient.

As used herein, “to treat” a condition or “treatment” of the conditionis an approach for obtaining beneficial or desired results, such asclinical results. Beneficial or desired results can include, but are notlimited to, alleviation or amelioration of one or more symptoms orconditions; diminishment of extent of disease, disorder, or condition;stabilized (i.e., not worsening) state of disease, disorder, orcondition; preventing spread of disease, disorder, or condition; delayor slowing the progress of the disease, disorder, or condition;amelioration or palliation of the disease, disorder, or condition; andremission (whether partial or total), whether detectable orundetectable. “Palliating” a disease, disorder, or condition means thatthe extent and/or undesirable clinical manifestations of the disease,disorder, or condition are lessened and/or time course of theprogression is slowed or lengthened, as compared to the extent or timecourse in the absence of treatment.

EXAMPLES

The following examples are exemplary and not intended to be limiting.The above disclosure provides many different embodiments forimplementing the features of the invention, and the following examplesdescribe certain embodiments. It will be appreciated that othermodifications and methods known to one of ordinary skill in the art canalso be applied to the following experimental procedures, withoutdeparting from the scope of the invention.

In the following examples, the following preparations were used, andprepared by the general methods described below:

(i) Preparation of 0.01N HCl acid media: 68 mL of concentratedhydrochloric acid was added to 8000 mL of water and mixed well.(ii) Preparation of 0.01N HCl media: 8.5 mL of concentrated hydrochloricacid was added to 1000 mL of water and mixed well.(iii) Preparation of pH 4.5 acetate buffer: 3.0 g of sodium acetatetrihydrate was dissolved in 1000 mL of water, and the pH was adjustedwith q.s. glacial acetic acid to a pH of 4.5±0.05.(iv) Preparation of McIlvaine buffer of pH 6.5 with 0.1% Tween 80: 204.8g of disodium hydrogen phosphate anhydrous and 52.8 g of citric acidanhydrous were dissolved in 10,000 mL of water, and the pH was adjustedwith q.s. ortho-phosphoric acid to a pH of 6.50±0.05. Then, 10 g ofTween 80 was added to the above solution and stirred until dissolvedcompletely.(v) Preparation of FaSSIF (Fasted state simulated intestinal fluid)stock solution: 2.53 g sodium hydroxide, 23.7 g sodium dihydrogenphosphate monohydrate, and 37.1 g sodium chloride were added to 3 L ofwater and mixed thoroughly. The pH was adjusted to a pH of 6.50±0.05with q.s. sodium hydroxide or q.s. hydrochloric acid. Then, 13.6 gFaSSIF powder was added to the above solution.(vi) Preparation of FeSSIF (Fed state simulated intestinal fluid) stocksolution: 20.2 g sodium hydroxide, 43.3 g glacial acetic acid, and 59.4g sodium chloride were added to 2.5 L of water and mixed thoroughly. ThepH was adjusted to a pH of 5.0±0.05 with q.s. sodium hydroxide or q.s.acetic acid. Then, 56.0 g FaSSIF powder was added to the above solution.

Example 1: Composition of Lurasidone

A lurasidone film-coated tablet was prepared, having the composition setforth in Table 1.

TABLE 1 Composition 1 Components (mg/unit) Granules of extrudate 1Lurasidone 29.79 Hypromellose acetate succinate (HPMC-AS) 89.37 Granulesof extrudate 2 Lurasidone 7.45 Kollidon ® VA 64 (PVP/VA) 22.35 Totalweight of granules of 148.95 extrudate 1 and extrudate 2 Extra-granularmaterial Microcrystalline cellulose 139.04 (Avicel PH102) Croscarmellosesodium 9 (Ac-Di-Sol) Aerosil 1.5 Magnesium stearate 1.5 Total weight 300OPADRY ® II white 9 Weight of film coated tablet 309

Manufacturing Procedure:

Preparation of granules of extrudate 1: The lurasidone and HPMC-AS weresifted together through a 25-mesh screen. The co-sifted material wasloaded into a blender and blended for 30 minutes at 10 rpm to obtain apremix blend. The premix blend was extruded in a hot melt extruder(Omicron 10P). The obtained extrude 1 was milled and passed through a60-mesh screen to provide granules of extrudate 1. FIG. 1 illustratesthe Powder X-Ray Diffraction (PXRD) pattern of the solid dispersioncomposition corresponding to extrudate 1 in composition 1.

Preparation of granules of extrudate 2: The lurasidone and PVP/VA weresifted through a 25-mesh screen. Then, the co-sifted material was loadedinto a blender and blended for 30 minutes at 10 rpm to obtain a premixblend. The premix blend was extruded in a hot melt extruder. Theobtained extrude 1 was milled and passed through a 60-mesh screen toprovide granules of extrudate 2. FIG. 2 illustrates the Powder X-RayDiffraction (PXRD) pattern of the solid dispersion compositioncorresponding to extrudate 2 in composition 1.

Extra-granular material: Microcrystalline cellulose, croscarmellosesodium and Aerosil were passed through a 40-mesh screen and added to ablender. Granules of extrudates 1 and 2 were added to the blender andblended for 10 minutes at 10 rpm to obtain a pre-lubricated blend.Magnesium stearate was sifted through a 60-mesh screen and added to thepre-lubricated blend in the blender, followed by blending for 5 minutesat 10 rpm to obtain a lubricated blend. The lubricated blend wascompressed into tablets. The tablets were coated with OPADRY® II white85F18422 aqueous dispersion.

Hot melt extrusion to prepare the granules of extrudate 1 and extrudate2 in the above manufacturing procedure was carried out using an Omicron10P extruder. The process parameters maintained during the hot meltextrusion process for extrudate 1 and extrudate 2 are given below inTable 2.

TABLE 2 Process parameter for preparing extrudate 1 & 2 Range Screwspeed 250-400 rpm Zone1 (Conveying Zone) 33-35° C. Zone2 (Blending zone)70-90° C. Zone3 (Mixing zone) 120-180° C. Zone4 (Conveying zone)120-180° C. Chiller roller temperature 20° C.

Example 2

A lurasidone hydrochloride film-coated tablet composition was prepared,having the composition set forth in Table 3.

TABLE 3 Composition 2 Components mg/unit Lurasidone Hydrochloride 40Hypromellose Acetate Succinate (HPMC-AS) 120 Intra-granular materialMicrocrystalline cellulose (Avicel PH 101) 110 Colloidal Silicon dioxide(Aerosil 200) 1.35 Magnesium stearate 1.35 Extra-granular materialMicrocrystalline cellulose (Avicel PH 102) 113.3 Croscarmellose Sodium(Ac-di-sol) 12 Magnesium stearate 2 Coating OPADRY ® II white 12 Total412

Manufacturing Procedure:

Step 1: The lurasidone HCl was added to methylene chloride in acontainer, and stirred until a clear solution was obtained. HPMC-AS andisopropyl alcohol (IPA) were added to the obtained solution, and stirreduntil a clear solution was obtained.

Step 2: The solution from step 1 was spray dried using a spray dryer toobtain a lurasidone solid dispersion. The spray drying processparameters are provided in Table 4A. FIG. 3 shows the Powder X-RayDiffraction (PXRD) pattern of the lurasidone solid dispersion incomposition 2.

Step 3: The lurasidone solid dispersion (from step 2), microcrystallinecellulose, and Aerosil were passed through a 40-mesh screen, added to ablender and blended for 20 minutes at 10 rpm to obtain a mixture.Magnesium stearate was passed through a 60-mesh screen, added to themixture and lubricated in a blender for 10 minutes at 10 rpm to obtain ablend for compaction.

Step 4: The blend from step 3 was compacted in a roller compactor. Theroller compaction process parameters are mentioned in Table 4B to obtaincompacts, which were milled and passed through a 30-mesh screen toobtain granules.

Step 5: Microcrystalline cellulose and croscarmellose sodium wereweighed, passed through a 40-mesh screen and blended with the granulesfrom step 4 for 10 minutes at 10 rpm to obtain a pre-lubricated blend.

Step 6 (Lubrication): Magnesium stearate was passed through a 60-meshscreen, added to the pre-lubricated blend of step 5, and lubricated for15 minutes at 10 rpm to obtain final blend.

Step 7: The final blend was compressed into a tablet and coated withOPADRY® II white 85F18422 aqueous dispersion.

Any suitable operating parameters conditions may be used for the abovesteps. For instance, the spray drying may be carried out using theparameters set forth in Table 4A.

TABLE 4A Parameters Typical value Typical ranges Total dissolved solids5%  3-7% Inlet Temperature (° C.) 75-77 70-80 Outlet Temperature (° C.)47-52 40-60 Atomization pressure (kg/cm²) 1.23-1.24 1.1-1.3 Inlet air(m³/hr) 80 75-85 Feed rate (mL/min) 5-7 4-8

Any suitable operating parameters conditions may be used for the abovesteps. For instance, the roller compaction may be carried out using thefollowing the parameters set forth in Table 4B.

TABLE 4B Roller compaction process parameters Range Pre-granulatorscreen (mm) 1.6 Fine granulator screen (mm) 1   Screw feeder (rpm) 27-33Fine granulator (rpm)  50-100 Roller speed (rpm) 4-8 Roller gap (mm) 1-4Hydraulic pressure (Bar)  40-100 Vacuum On Roller gap control On Flakecrusher On

Example 3

Hot-melt extruded formulations containing enteric polymer, solublepolymer and optional surfactant were prepared, having the compositionsset forth in Table 5.

TABLE 5 Composition 3 4 Component mg/unit mg/unit Granules of Extrudate:Lurasidone 37.2 37.2 HPMC-AS 111.7 111.7 Hydroxypropyl cellulose 22.322.3 Sodium lauryl sulfate 9.3 — Extra-granular Material:Microcrystalline cellulose (Avicel PH 102) 139.04 139.04 Croscarmellosesodium (Ac-Di-Sol) 9 9 Aerosil Pharma 200 1.5 1.5 Magnesium Stearate 1.51.5 Total weight 331.54 322.24 Coating: OPADRY ® II white 9.93 9.66Total weight of film-coated tablet 341.47 331.9

Manufacturing Procedure:

Lurasidone (free base), HPMC-AS, hydroxypropyl cellulose, and optionallysodium lauryl sulfate were weighed in the quantities as shown in Table5, and physically mixed in a polybag. The mixture was then placed in anextruder hopper. The Omicron 10P extruder used has a single screw solidconveying mechanism that extends from the hopper through multipleheating zones to the extrusion die. The mixture was passed through theheated extruder at a temperature range from about 29° C. to about 170°C., as determined by temperature setting of the extruder heating zonesso that melting or softening of the mixture occurred. An extruder torqueand screw speed were used as shown in Table 2. The resulting extrudatewas cooled to room temperature and crushed. Then the crushed materialwas passed through a 40-mesh screen.

Microcrystalline cellulose, croscarmellose sodium, and Aerosil werepassed through a 40-mesh screen and added to a blender. The granules ofthe extrudate were added to a blender and blended for 10 minutes at 10rpm to obtain a pre-lubricated blend. Magnesium stearate was siftedthrough a 60-mesh screen and added to the pre-lubricated blend in theblender, and blended for 5 minutes at 10 rpm to obtain a lubricatedblend. The lubricated blend was compressed into tablets.

The tablets were coated with OPADRY® II white 85F18422 aqueousdispersion.

Example 4

An open-label, balanced, randomized, single-dose, two-treatment,three-period, three-sequence, three-way crossover oral relativebioavailability study of Composition 1 and LATUDA® tablets (40 mg) wasconducted in 21 normal, healthy, adult human subjects, under fasting andfed conditions.

TABLE 6 Composition Pharmaco- Composition 1 (Fast)/ kinetic 1 LATUDA ®LATUDA ® parameter (Fast) (Fed) (Fed) (%) 90% CI C_(max) 74.33 89.0783.45 71.88-96.88 (ng/mL) AUC_(0-t) 305.5 418.68 72.97 66.67-79.86 (ng ·hr/mL) AUC_(0-∞) 329.45 463.14 71.13 64.89-77.99 (ng · hr/mL)

TABLE 7 Composition Pharmaco- Composition 1 (Fed)/ kinetic 1 LATUDA ®LATUDA ® parameter (Fed) (Fed) (Fed) (%) 90% CI C_(max) 80.12 89.0789.95 77.49-104.41 (ng/mL) AUC_(0-t) 425.78 418.68 101.7 93.97-110.06(ng · hr/mL) AUC_(0-∞) 459.85 462.12 99.51 91.45-108.27 (ng · hr/mL)

TABLE 8 Pharmaco- Composition kinetic Composition 1 1 fast/fed parameterN Fast Fed (%) 90% CI C_(max) 16 74.33 80.12 92.77  78.80-109.24 (ng/mL)AUC_(0-t) 16 305.5 425.78 71.76 64.69-79.58 (ng · hr/mL) AUC_(0-∞) 13329.45 459.85 71.64 63.81-79.19 (ng · hr/mL)

Example 5

A study was conducted to test the pharmacokinetics and bioavailabilityof a Composition 2 in healthy human subjects, with the subjects ineither a fed or a fasted state. The effect of food on bioavailabilityfrom a single oral dose of the lurasidone hydrochloride tablet ofcomposition 2 was evaluated.

An open-label, balanced, randomized, single-dose, two-treatment,three-period, three-sequence, three-way crossover oral relativebioavailability study of Composition 2 and LATUDA® tablets 40 mg wasconducted in 21 normal, healthy, adult, human subjects under fasting andfed conditions.

TABLE 9 Composition Pharmaco- Composition 2 (fast)/ kinetic 2 LATUDA ®LATUDA ® parameter (Fast) (Fed) (Fed) (%) 90% CI C_(max) 94.42 109.4686.27  72.43-102.74 (ng/mL) AUC_(0-t) 308.6 442.51 69.74 63.34-76.78 (ng· hr/mL) AUC_(0-∞) 331.24 480.95 68.87 62.64-75.72 (ng · hr/mL)

TABLE 10 Composition Pharmaco- Composition 2 (Fed)/ kinetic 2 LATUDA ®LATUDA ® parameter (Fed) (Fed) (Fed) (%) 90% CI C_(max) 75.28 109.4668.77 60.59-78.06 (ng/mL) AUC_(0-t) 400.00 442.51 90.39 84.26-96.97 (ng· hr/mL) AUC_(0-∞) 430.87 480.95 89.59 83.58-96.02 (ng · hr/mL)

TABLE 11 Composition PK Composition 2 2 fast/fed parameter N Fast Fed(%) 90% CI C_(max) 20 94.42 75.28 125.43 104.61-150.40 (ng/mL) AUC_(0-t)20 308.6 400.00 77.15 71.06-83.77 (ng · hr/mL) AUC_(0-∞) 18 331.24430.87 76.88 70.90-83.36 (ng · hr/mL)

Example 6

Dissolution profiles of LATUDA® tablets and Composition 2 in 0.01N HClacid media, followed by FaSSIF media of pH 6.5

Dissolution analysis was carried out in a USP type II dissolution bath(VanKel) using 500 mL of 0.01N HCl kept at 37° C. for 60 minutes andfollowed by 500 mL FaSSIF media of pH 6.5 for 60 minutes at 37° C. andstirred at 75 rpm. Samples were taken at 5, 10, 20, 45, and 60 minutesfrom 0.01N HCl media and 65, 70, 80, 105 and 120 minute time points fromFaSSIF media of pH 6.5 and analyzed using HPLC system with UVspectrophotometer at a wavelength 232 nm. The results of themeasurements are given in Table 12 and shown graphically in FIG. 4.

TABLE 12 Dissolution Time in % of Drug released Media minutes LATUDA ®Composition 2 Acid media 0 0 0 (0.01N HCl 5 54 46 media) 10 96 62 20 10274 45 105 84 60 106 91 FaSSIF media 65 85 72 of pH 6.5 70 85 71 80 76 73105 54 65 120 43 58

Dissolution Profiles of LATUDA® Tablets and Composition 2 in 0.01N HClAcid Media, Followed by FeSSIF Media of pH 5.0

Dissolution analysis was carried out in a USP type II dissolution bath(VanKel) using 500 mL of 0.01N HCl kept at 37° C. for 60 minutes andfollowed by 500 mL FeSSIF media of pH 5.0 for 60 minutes at 37° C. andstirred at 75 rpm. Samples were taken at 5, 10, 20, 45, and 60 minutesfrom 0.01N HCl media and 65, 70, 80, 105 and 120 minute time points fromFeSSIF media of pH 5.0 and analyzed using HPLC system with UVspectrophotometer at a wavelength 232 nm. The results of themeasurements are given in Table 13 and shown graphically in FIG. 5.

TABLE 13 Dissolution Time in % of Drug released Media minutes LATUDA ®Composition 2 Acid media 0 0 0 (0.01N HCl 5 51 43 media) 10 96 62 20 10276 45 104 87 60 108 92 FeSSIF media 65 100 86 of pH 5.0 70 101 75 80 10275 105 104 74 120 106 76

Example 7 Dissolution Profiles of LATUDA® Tablets, Compositions 1, 3 and4 in 0.01N HCl Acid Media, Followed by FaSSIF Media of pH 6.5

Dissolution analysis was carried out in a USP type II dissolution bath(VanKel) using 500 mL of 0.01N HCl kept at 37° C. for 60 minutes andfollowed by 500 mL FaSSIF media of pH 6.5 for 60 minutes at 37° C. andstirred at 75 rpm. Samples were taken at 5, 10, 20, 45, and 60 minutesfrom 0.01N HCl media and 65, 70, 90, 105 and 120 minute time points fromFaSSIF media of pH 6.5 and analyzed using HPLC system with UVspectrophotometer at a wavelength 232 nm. The results of themeasurements are given in Table 14 and shown graphically in FIG. 6.

TABLE 14 % of Drug released Dissolution Time Composition Media (minutes)Latuda ® 1 3 4 Acid media 0 0 0 0 0 (0.01N HCl 5 54 29 28 33 media) 1096 36 42 47 20 102 44 54 62 45 105 59 63 78 60 106 65 64 81 FaSSIF media65 85 54 88 77 (pH 5.0) 70 85 70 88 78 90 76 57 88 80 105 54 62 87 82120 43 50 87 85 130 — — 88 88

Dissolution Profiles of LATUDA® Tablets and Composition 1 in 0.01N HClAcid Media, Followed by FeSSIF Media of pH 5.0

Dissolution analysis was carried out in a USP type II dissolution bath(VanKel) using 500 mL of 0.01N HCl kept at 37° C. for 60 minutes andfollowed by 500 mL FeSSIF media of pH 5.0 for 60 minutes at 37° C. andstirred at 75 rpm. Samples were taken at 5, 10, 20, 45, and 60 minutesfrom 0.01N HCl media and 65, 70, 90, 105 and 120 minute time points fromFeSSIF media of pH 5.0 and analysed using HPLC system with UVspectrophotometer at a wavelength 232 nm. The results of themeasurements are given in Table 15 and shown graphically in FIG. 7.

TABLE 15 Dissolution Time in % of Drug released Media minutes Latuda ®Composition 1 Acid media 0 0 0 (0.01N HCl 5 51 23 media) 10 96 29 20 10233 45 104 45 60 108 50 FeSSIF media 65 100 50 of pH 5.0 70 101 50 90 10249 105 104 49 120 106 49

Example 8 Dissolution Profiles of Latuda Tablets, Compositions 1, 3 and4 in McIlvaine Buffer Media of pH 6.5

Dissolution analysis was carried out in a USP type II dissolution bath(VanKel) using 1000 mL of McIlvaine buffer media of pH 6.5 kept at 37°C. for 120 minutes and stirred at 75 rpm. Samples were taken at 5, 10,20, 45, 60, 75, 90, 105 and 120 minutes and analysed using HPLC systemwith UV spectrophotometer at a wavelength 232 nm. The results of themeasurements are given in Table 16 and shown graphically in FIG. 8.

TABLE 16 Time in minutes Latuda ® Composition 1 Composition 3Composition 4 0 0 0 0 0 5 3 38 78 72 10 5 59 73 75 20 8 63 66 58 45 9 4865 45 60 11 34 64 42 75 12 33 64 40 90 13 32 64 40 105 14 32 64 39 12015 32 64 40

Dissolution Profiles of LATUDA® Tablets, Composition 1, 3 and 4 inFaSSIF Media of pH 6.5

Dissolution analysis was carried out in a USP type II dissolution bath(VanKel) using 1000 mL of FaSSIF media of pH 6.5 kept at 37° C. for 120minutes and stirred at 75 rpm. Samples were taken at 5, 10, 20, 45, 60,75, 90, 105 and 120 minutes and analyzed using HPLC system with UVspectrophotometer at a wavelength 232 nm. The results of themeasurements are given in Table 17 and shown graphically in FIG. 9.

TABLE 17 Time in minutes LATUDA ® Composition 1 Composition 3Composition 4 0 0 0 0 0 5 13 12 74 7 10 13 40 83 20 20 14 73 85 53 45 1484 83 86 60 14 82 80 85 75 14 80 77 82 90 14 78 74 78 105 13 75 71 74120 13 71 69 70 130 14 — 66 65

Dissolution Profiles of LATUDA® Tablets, Compositions 1 and 2 in 0.1NHCl Acid Media

Dissolution analysis was carried out in a USP type II dissolution bath(VanKel) using 500 mL of 0.1 N HCl acid media kept at 37° C. for 60minutes and stirred at 75 rpm. Samples were taken at 5, 10, 20, 45 and60 minutes and analyzed using HPLC system with UV spectrophotometer at awavelength 232 nm. The results of the measurements are given in Table 18and shown graphically in FIG. 10.

TABLE 18 Time in minutes Composition 1 Composition 2 LATUDA ® 0 0 0 0 530 30 53 10 34 39 75 20 38 48 85 45 44 57 92 60 45 59 92

Dissolution Profiles of LATUDA® Tablets, Compositions 1 and 2 in AcetateBuffer of pH 4.5

Dissolution analysis was carried out in a USP type II dissolution bath(VanKel) using 1000 mL of acetate buffer of pH 4.5 kept at 37° C. for 60minutes and stirred at 75 rpm. Samples were taken at 5, 10, 20, 45, 60,90 and 120 minutes and analyzed using HPLC system with UVspectrophotometer at a wavelength 232 nm. The results of themeasurements are given in Table 19 and shown graphically in FIG. 11.

TABLE 19 Time in minutes LATUDA ® Composition 1 Composition 2 0 0 0 0 529 15 14 10 50 20 19 20 55 25 26 45 56 28 36 60 56 29 40 70 55 30 42 9055 30 44 120 54 31 48

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that it can be performed within awide equivalent range of parameters without affecting the scope of theinvention or any embodiment thereof. All publications, patentapplications and patents disclosed herein are incorporated by referencein their entirety.

Unless specified otherwise, all the percentages, portions and ratios inthe present invention are on weight basis.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the present specification and associated claims areto be understood as being modified in all instances by the term “about.”Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the embodiments of the present invention.Whenever a numerical range with a lower limit and an upper limit isdisclosed, any number and any included range falling within the range isspecifically disclosed. In particular, every range of values (of theform, “from about a to about b,” or, equivalently, “from approximately ato b,” or, equivalently, “from approximately a-b”) disclosed herein isto be understood to set forth every number and range encompassed withinthe broader range of values. Also, the terms in the claims have theirplain, ordinary meaning unless otherwise explicitly and clearly definedby the patentee. Moreover, the indefinite articles “a” or “an,” as usedin the claims, are defined herein to mean one or more than one of theelement that it introduces.

While compositions and methods are described herein in terms of“comprising” various components or steps, the compositions and methodscan also “consist essentially of” or “consist of” the various componentsand steps.

1. A pharmaceutical composition comprising a solid dispersion ofamorphous lurasidone in a pharmaceutically acceptable carrier, whereinthe pharmaceutically acceptable carrier is selected from the groupconsisting of hydroxypropyl methyl cellulose acetate succinate(HPMC-AS), polyvinyl pyrrolidine vinyl acetate (PVP/VA) copolymer,hydroxypropyl methylcellulose phthalate (HPMCP), and mixtures thereof;and wherein the pharmaceutical composition may be administered to ahuman subject in either fed or fasted state.
 2. The pharmaceuticalcomposition according to claim 1, wherein at least one pharmacokineticparameter in the fasted state is from about 70% to about 143% of thatpharmacokinetic parameter in the fed state; and wherein the at least onepharmacokinetic parameter is selected from AUC_(0-infinity), C_(max),T_(max), AUC_(0-t), or combinations thereof.
 3. The pharmaceuticalcomposition according to claim 1, wherein the solid dispersion ofamorphous lurasidone is prepared by hot-melt extrusion, spray-drying orco-precipitation.
 4. The pharmaceutical composition according to claim1, wherein the solid dispersion of amorphous lurasidone has a weightratio of the lurasidone or pharmaceutically acceptable salt thereof tothe pharmaceutically acceptable carrier from about 1:1 to about 1:6. 5.The pharmaceutical composition according to claim 1, wherein the soliddispersion of amorphous lurasidone has a weight ratio of the lurasidoneor pharmaceutically acceptable salt thereof to the pharmaceuticallyacceptable carrier from about 1:2 to about 1:4.
 6. The pharmaceuticalcomposition according to claim 1, wherein the solid dispersion ofamorphous lurasidone has a weight ratio of the lurasidone orpharmaceutically acceptable salt thereof to the pharmaceuticallyacceptable carrier of about 1:3.
 7. The pharmaceutical compositionaccording to claim 1, wherein the pharmaceutical composition comprisesfrom about 50 mg to about 400 mg of lurasidone or pharmaceuticallyacceptable salt thereof.
 8. The pharmaceutical composition according toclaim 1, wherein the pharmaceutical composition is in the form of atablet, a capsule, a caplet, beads, granules or oral suspension.
 9. Thepharmaceutical composition according to claim 8, wherein thepharmaceutical composition is in the form of a tablet, and wherein thetablet comprises (a) granules of the solid dispersion of amorphouslurasidone, (b) at least one extra-granular excipient, and (c)optionally, a tablet coating.
 10. The pharmaceutical compositionaccording to claim 9, wherein the granules of the solid dispersion ofamorphous lurasidone comprise at least a first portion of granulescomprising lurasidone and hypromellose acetate succinate, and at least asecond portion of granules comprising lurasidone and PVP/VA copolymer.11. The pharmaceutical composition according to claim 9, wherein the atleast one extra-granular excipient comprises microcrystalline cellulose,croscarmellose sodium (Ac-Di-Sol), and colloidal silicon dioxide. 12.The pharmaceutical composition according to claim 9, wherein thegranules of the solid dispersion of amorphous lurasidone furthercomprise at least one intra-granular excipient.
 13. The pharmaceuticalcomposition according to claim 12, wherein the at least oneintra-granular excipient comprises microcrystalline cellulose,croscarmellose sodium (Ac-Di-Sol), and colloidal silicon dioxide. 14.The pharmaceutical composition according to claim 12, wherein the atleast one extra-granular excipient comprises microcrystalline cellulose,and croscarmellose sodium (Ac-Di-Sol).
 15. The pharmaceuticalcomposition according to claim 1, wherein the pharmaceutical compositionis obtained by direct compression, wet granulation or dry granulation.16. The pharmaceutical composition according to claim 1, furthercomprising at least one excipient selected from the group consisting ofbinders, solubilizers, disintegrating agents, lubricants, colorants,surfactants and mixtures thereof.
 17. A method for treating a CNSdisorder in a human, which method comprises administering apharmaceutical composition according to claim 1 to a patient in a fastedor fed state.
 18. A pharmaceutical composition comprising a soliddispersion of amorphous lurasidone in a pharmaceutically acceptablecarrier, wherein the pharmaceutically acceptable carrier furthercomprises a solubilizer, a surfactant, or a mixture thereof, and whereinthe pharmaceutical composition may be administered to a human subject ineither fed or fasted state.
 19. The pharmaceutical composition accordingto claim 18, wherein the pharmaceutical composition is in the form of atablet, and wherein the tablet comprises (a) granules of the soliddispersion of amorphous lurasidone, (b) at least one extra-granularexcipient, and (c) optionally, a tablet coating.
 20. The pharmaceuticalcomposition according to claim 19, wherein the granules of the soliddispersion comprise lurasidone, hydroxypropyl methyl cellulose acetatesuccinate (HPMC-AS), hydroxypropyl cellulose (HPC), and optionally,sodium lauryl sulfate.
 21. The pharmaceutical composition according toclaim 19, wherein the at least one extra-granular excipient comprisesmicrocrystalline cellulose, croscarmellose sodium (Ac-Di-Sol), andcolloidal silicon dioxide.
 22. A pharmaceutical composition comprising asolid dispersion of amorphous lurasidone in a pharmaceuticallyacceptable carrier, wherein the in vitro dissolution rate is less thanabout 50% in 60 minutes, and wherein the in vitro release rate is chosensuch that the peak plasma levels of lurasidone obtained in vivo occursbetween about 1 and about 6 hours after administration of thecomposition to a patient.
 23. The pharmaceutical composition of claim22, wherein the in vitro dissolution rate is determined using a USPpaddle method of 75 rpm in 500 ml 0.1 N HCl at 37° C.
 24. Thepharmaceutical composition of claim 22, wherein the in vitro dissolutionrate is determined using a USP paddle method of 75 rpm in 1000 ml 4.5 pHacetate buffer at 37° C.
 25. A pharmaceutical composition comprising asolid dispersion of amorphous lurasidone in a pharmaceuticallyacceptable carrier, wherein at least one pharmacokinetic parameter inthe fasted stated is from about 70% to about 143% of thatpharmacokinetic parameter in the fed state; and wherein the at least onepharmacokinetic parameter is selected from AUC_(0-infinity), C_(max),T_(max), AUC_(0-t), or combinations thereof.
 26. The pharmaceuticalcomposition of claim 25, wherein the AUC_(0-infinity) of lurasidone in ahuman subject subsequent to administration in the fasted state is fromabout 80% to about 125% of the AUC_(0-infinity) of lurasidone in a humansubject subsequent to administration in the fed state.
 27. Thepharmaceutical composition according to claim 25, wherein the AUC_(0-t)of lurasidone in a human subject subsequent to administration in thefasted state is from about 80% to about 125% of the AUC_(0-t) oflurasidone in a human subject subsequent to administration in the fedstate.
 28. The pharmaceutical composition according to claim 25, whereinthe C_(max) of lurasidone in a human subject subsequent toadministration in fasted state is from about 80% to about 125% of theC_(max) of lurasidone in a human subject subsequent to administration inthe fed state.
 29. The pharmaceutical composition according to claim 25,wherein the T_(max) of lurasidone in a human subject subsequent toadministration in fasted state is from about 80% to about 125% of theT_(max) of lurasidone in a human subject subsequent to administration inthe fed state.